Apicomplexan parasites are responsible for high impact human diseases such as malaria, toxoplasmosis and cryptosporidiosis.
These obligate intracellular pathogens are dependent on both
lipid biosynthesis as well as the uptake of host
lipids for biogenesis of parasite membranes and the membranes of vacuoles within which they reside. Genome annotations
and biochemical studies indicate that apicomplexan parasites can synthesize fatty acids via a number of different biosynthetic
pathways that are differentially compartmentalized. However, the relative contribution of each of these biosynthetic pathways
to total fatty acid composition of intracellular parasite stages remains poorly defined. Here we use a combine metabolomics
with genetic and biochemical approaches to delineate the contribution of fatty acid biosynthetic pathways in
. Metabolic labeling studies with
C-acetate showed that intracellular tachyzoites synthesized a range
of long and very long chain fatty acids (C14:0-26:1). Genetic disruption of type II fatty acid synthase (FASII) resulted in
greatly reduced synthesis of saturated fatty acids up to eighteen carbons long, leading to reduced intracellular growth that
was partially restored by addition long chain fatty acids. In contrast, synthesis of very long chain fatty acids was primarily
dependent on a fatty acid elongation system comprising three elongases, two reductases and a dehydratase that were localized
to the endoplasmic reticulum. The function of these enzymes was confirmed by metabolomics and heterologous expression in
yeast. This elongase pathway appears to have a unique role in generating very long unsaturated fatty acids (C26:1) that cannot
be salvaged from the host.
James MacRae completed his PhD in 2005 at the University of Dundee, Scotland, studying the surface glycoconjugates and glycobiology of
Trypanosoma cruzi. He then attained a Royal Society Fellowship in the laboratory of Professor Malcolm McConville at the University of Melbourne,
where he has been leading development of metabolomic approaches in the investigation of, and identification of potential drug targets in, protozoan
parasites, including Plasmodium falciparum, Toxoplasma gondii, Leishmania spp and fungi. He is also collaborating closely with Metabolomics
Australia (a government-funded nationwide initiative) in order to develop systems biology techniques.
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